(introductory text...)

Studies of the long-term effects of intrauterine growth
retardation on mental performance and behavior are reviewed. The results of the
majority of studies suggest that, if effects of prematurity and of other
associated complicating factors are controlled for, effects of IUGR per se, that
can sometimes be demonstrated at an earlier age, become diluted by
socio-environmental conditions at later stages in life and no longer appear to
have a detrimental effect on mental and behavioral outcomes in adolescence and
adulthood.

Studies of the long-term effects of intrauterine growth
retardation (IUGR) on mental performance and behavior have provided varying and
often conflicting results. This is mainly due to the heterogeneity of the
populations that have been studied, including different definitions and varying
causes of IUGR, differences in perinatal and neonatal complications associated
with the gestational age of the child, and differences in the quality of
neonatal care. Initial reports of the consequences of IUGR included children
with major congenital malformations and children with intrauterine infections,
who are known to have very poor developmental outcomes (Allen, 1984; Warkany
et al, 1966). Furthermore postnatal conditions may confound the effects
of IUGR on later mental performance and behavior. These include subnormal
nutrition and growth during infancy and early childhood, and the social and
environmental conditions of the family (Allen, 1984; Smeriglio, 1989). Reported
heterogeneity of outcomes of IUGR is further influenced by the fact that some
studies are population based, whereas others include only selected high-risk
hospital populations. Many studies include both preterm and term children, and
some include multiple births. The loss to follow-up sometimes exceeds 50%, thus
populations followed might not be representative of the original population.

The majority of available reports of adolescent and adult outcomes
of IUGR populations pertain to births that occurred prior to the development of
current methods of perinatal and neonatal care, when infant mortality was very
high. Furthermore, between 1940 and 1960, various practices of newborn care
caused iatrogenic sequelae that had a detrimental effect on outcomes. These
included prolonged starvation of babies, unrestricted use of oxygen that
resulted in blindness, followed by a period of restricted use of oxygen
resulting in higher death rates and cerebral palsy, and the widespread use of
antibiotics, especially sulfa drugs causing kernicterus and streptomycin causing
dearness (Hack et al, 1979; Douglas and Gear, 1976). Current methods of
perinatal care include antenatal surveillance of intrauterine growth failure and
associated fetal distress, optimal timing of delivery, adequate neonatal
resuscitation and the prevention and treatment of neonatal complications
associated with IUGR such as hypoglycemia and polycythemia (Kramer et al,
1990; Hawdon et al, 1990; Tenovuo et al, 1988). There is currently
a greater awareness of the importance of the home environment and socioeconomic
status of the family as determinants of childhood and adult outcomes (Sameroff
et al, 1993).

This report will review the published literature on the mental
performance and behavior of adolescent and adult persons who experienced
intrauterine growth
retardation.

School age outcomes of young adolescents with intrauterine growth failure (Table 1)

Drillien (1970) in Scotland compared 10- to 12-year-old IUGR
children born 1953-1958 at term gestation to normal birthweight controls. The
results were confounded by the fact that mothers of IUGR children tended to be
of lower social class and of shorter stature than mothers of normal birthweight
children, and that mothers of children with birthweights < 2000 g had higher
rates of severe toxemia and chronic illness. No differences in intelligence were
found among IUGR children of the middle to upper working classes, whereas IUGR
children of mothers in the lower working classes had lower intelligence scores
than normal birthweight children.

Hill (1978) in the USA, examined children born 1964-1965 who were
clinically malnourished or 'dysmature' at term birth, and compared them to
normal controls. At 12 to 14 years of age the IUGR children had significantly
lower mean IQ scores, 42% had either mental retardation or learning difficulties
and 27% required special education compared to none of the controls. Although
children with chromosomal anomalies and congenital malformations were excluded
from study, the IUGR children had a history of neonatal complications including
low Apgar scores and hypoglycemia, which might have affected the later outcomes.

No significant differences in mental or behavioral handicaps. IQ
of < 2000 gm group 93 vs 97 for controls. No significant effect of IUGR on
outcomes.

Baker '87

Denmark

'59-'61

18

Report on 94 of 857 < 2.5 kgm, term and preterm

No difference between LBW or IUGR groups and
controls.

Westwood et al (1983) in Canada, reported outcomes in 13-
to 19-year-old children, born 1960-1966 at term gestation, who had severe IUGR
(below -2SD birthweight for gestation). Children with intrauterine infections,
major congenital malformations and severe asphyxia, as well as twins, were
excluded from study. Of an eligible cohort of 118 children, only 33 (28%) were
followed to adolescence. Results revealed significantly lower IQ scores among
the IUGR children as compared to controls, but these differences were not
significant after controlling for socio-economic status of the families. There
were, however, significant differences on arithmetic achievement scores. This
population had previously been followed to 8 years of age by Fitzhardinge, at
which time greater differences were reported between the IUGR population and
controls (Fitzhardinge and Steven, 1972). Westwood hypothesized that the
improved outcomes documented during adolescence resulted from resolution of some
difficulties with increasing age and maturity (Westwood et al, 1983).

Rantakallio (1988) in Finland examined the effect of intrauterine
growth failure on the school performance of a regional population of 12,000
children born in 1966. At 14 years of age, children with a birthweight for
gestational age below the median (25th-75th centile) had significantly higher
rates of educational subnormality, including mental retardation, cerebral palsy,
epilepsy, and delayed or no schooling. The rates of subnormality were higher for
preterm than for term born IUGR children, and highest for the children whose
birthweight percentiles were more than - 2 SD below the mean.

Lagerstrom in Sweden similarly examined the regional outcome of
IUGR children born between 1954 and 1956. In this population, only 7 of the 780
children born at term gestation (> 37 weeks) weighed < 2.5 kg at birth. At
13 years of age, these 7 children had significantly poorer scores on measures of
school performance, including intelligence, language, and mathematics
(Lagerstrom et al, 1991).

Illsley in Scotland, examined the outcomes of a regional
population of children born during 1969 and 1970. At 10 years of age, term born
IUGR children had IQ scores similar to the normal birthweight controls but had
poorer scores on tests of sensorimotor performance (Illsley and Mitchell, 1984).

Hawdon et al (1990) in England, examined the outcomes of a
regional population of children born 1973-1974. Thirty singleton boys out of an
initial population of 53 children born at term gestation were examined at 10-11
years of age. Intrauterine growth failure was defined as birthweight below - 2
SD for gestational age. Two (7%) of the boys were severely retarded and excluded
from further analyses. The remaining children had similar IQ and reading scores
when compared to matched controls. Significant correlations between lower
z-scores and behaviors suggestive of attention deficit disorder were noted when
the severity of weight for gestation was examined via z-scores (indicating the
deviation of the child's birthweight from the mean of gestational age). However,
although the groups had been matched for social class (father's occupation and
marital status of the mother), the mothers of the IUGR group were significantly
shorter in stature, smoked more, had higher rates of fetal distress and birth
complications, higher scores on questionnaires indicating 'neuroticism' and
'malaise', and the ratings of their involvement in the home were lower, with
significantly higher punishment scores. When multivariate analyses were
performed, the severity of intrauterine growth failure was the poorest predictor
of outcome, and predicted only the behaviors 'distractibility' and
'approachability'. The two best predictors of outcome were maternal intelligence
and the ordinal position of the child, followed by maternal height and the
family's occupational class. Neligan et al (1976) had reported on a
similar population born in the same area 10 years previously who had poorer
outcome at age 5-7 years. Hawdon hypothesized that the improved outcomes of his
IUGR population were due to improved neonatal care, consideration of the effects
of socio-environmental factors and the possibility that some findings might
disappear as adolescence approaches.

Low et al (1992) in Canada examined the outcomes of 50% of
a hospital population of IUGR children born 1978-1982 who were followed to 9-11
years of age. Both term and preterm children with IUGR (weight less than the
10th percentile for gestational age) had significantly higher rates of learning
difficulties compared to children who were appropriately grown at birth.
Socio-economic status, as measured by parental education and paternal
occupation, and rating of the child's inattention, also had a significant
independent association with learning problems.

Pryor et al (1995) examined 91 singleton IUGR children
(weight less than the 10th percentile at > 37 weeks gestation) born
1972-1973, and compared them to 1037 normal birthweight controls. With the
exception of one child, all had a normal neonatal course and none of the IUGR
children had malformations. At 15 years of age the IUGR children had
significantly lower mean WISC.R IQ scores, although their reading scores were
similar. Overall behavior and inattention, as measured on a behavior problem
checklist, differed significantly between groups.

Agarwal et al (1995) examined the combined effects of low
birthweight (< 2.5 kg) and childhood malnutrition on tests of cognitive
function at age 10-12 in a population of Indian boys. Results revealed that the
effect of IUGR was confounded by ongoing malnutrition during infancy and early
childhood. Children malnourished during infancy, irrespective of whether they
were of low birthweight, had deficits in memory tests, lower scores for
abilities related to personal and current information, orientation, and
conditional learning.

Mervis et al (1995) used a case control method to assess
the association between low birthweight, intrauterine growth failure and mental
retardation at 10 years of age in the metropolitan Atlanta Developmental
Disability Study in the USA. With full term normal birthweight children as the
reference population, the odds ratio for mild mental retardation (IQ 50-69) for
children born weighing 1.5 to 2.49 kg at term gestation was 2.2 (95% Confidence
Intervals, 1.2, 4.0) and the odds ratio for severe mental retardation (IQ <
50) was 3.7 (95 C.I. 1.7, 7.9). It is unclear whether children with intrauterine
infections were excluded from the
population.

Late adolescent and adult outcomes of low birthweight and intrauterine growth failure

The majority of studies on adult outcomes of children born with
low birthweight (< 2.5 kg) include both term and preterm children. Prior to
the 1960's the mortality of preterm infants was extremely high, and
low-birthweight populations included mainly borderline preterm and term
survivors, but only one report specifies the gestational age of the children at
birth (Paz et al, 1995).

The longest follow-up study is by Martyn et al (1996), who
reported on the relationship between fetal growth and cognitive function in
middle and late adult life. His population included 1576 singleton men and
women, aged 48-74 years, born to married mothers between the years 1920 and 1943
in Herefordshire, Preston and Sheffield, England, on whom birth measurements
were available, and who were still living in the area at the time of the
follow-up study. The population represented 47% of those who were invited to
participate in the study at middle age. Only 74 of the participants weighed less
than 5.5 pounds at birth and only 84 were born at less than 38 weeks gestation.
The study assessed cognitive function, and its decline with age, by measuring
the difference between a vocabulary test, which remains stable with age (the
Mill Hill test), and the AH 4 test which measures logical, verbal and numerical
reasoning and declines with age. Although cognitive function tended to be higher
with increasing birthweight, the results of the study revealed no significant
association between body size, or body proportion, at birth and cognitive
function, or its decline with age. However, subjects who had a larger biparietal
diameter at birth, had significantly higher AH 4 scores. This finding persisted
even when adjustment was made for the subject's age and social class and when
the subjects born before 38 weeks gestation were excluded from analysis. The
authors could not explain this finding since no significant relationship between
cognitive function and other head measurements (circumference or occipital
frontal diameter), or their relationship to other body measurements was found.
They concluded that, "by the time the baby reaches adulthood environmental
factors in postnatal life may overshadow any effect of the intrauterine
experience".

Stein et al (1972) studied the effects of prenatal exposure
to famine in Holland during World War II (1944-1945). The study population
included 125,000 males born in 7 famine-stricken areas and 11 areas not exposed
to famine, on whom psychological and educational tests were performed at
induction into the military at 18-19 years of age. Ninety-six percent of the
births were located for the study. The authors noted a decrease in mean
birthweight and birthweight below 2000 g during the famine, however there were
no differences in intelligence, measured by the Raven Progressive Matrices Test,
or in the rates of mild or severe mental retardation, between subjects from the
famine and control areas. Stein et al concluded that starvation during pregnancy
had no effects on intelligence and that there was no clear association between
mean birthweight and intelligence. During the famine, births decreased more
among the lower than among the higher social classes, whereas after the famine,
there was a compensatory increase in births among the lower social classes.
Social class effects might thus have affected the mean intelligence scores both
during and after the famine. Stein also noted that the population might
represent a selective survival of the fittest or that postnatal experiences
might have had a compensatory effect on the outcomes.

Douglas and Gear (1976) followed 80 of 163 singleton survivors
with birthweight less than 2000 g who participated in the 1959 longitudinal
British Birth Cohort Child Development Study. Sixty-seven subjects (84%) were
tested at 18 years of age and compared to matched controls with normal
birthweight. Although significant differences in academic performance had been
noted at 8 years of age, no significant differences in the rates of mental or
behavioral handicaps were noted later. At the age of 15 years the low
birthweight children had a mean IQ of 93 compared to 97 for the normal
birthweight controls, but this difference was not statistically significant.
Douglas noted that the results might have been confounded by the fact that,
although the groups had initially been matched by social class, the home
circumstances of the control families improved over the years, "possibly due to
a greater drive and social responsibility among these families". A similar
divergence of social circumstances between the low birthweight and control
families over time was noted by Illsley and Mitchell (1984).

Nilsen et al (1984) in Norway examined the outcomes of a
hospital population of children born 1962-1963 with birthweights < 2500 g,
when they were conscripted to the army at the age of 18 years. Twenty-nine
children had birthweights below the 10th centile for gestation; two of them were
considered unfit for military service. No differences in intelligence scores
were noted between the remaining 27 IUGR subjects and controls.

Paz et al (1995) reported on the outcomes of 17-year-old
IUGR (< 3rd percentile for gestation) term subjects born in Jerusalem,
Israel, who were tested prior to conscription to the army. The IUGR subjects had
significantly lower IQ scores when compared to controls, but when the scores
were adjusted for perinatal risk factors and socio-demographic status, the
differences remained significant for females only. The conclusions that can be
drawn from this study are limited by the: small number of IUGR children (30
males and 34 females), the exclusion of severely handicapped children from the
army evaluation, and the greater likelihood of females with low education
achievement to be exempt from conscription to the army. Significantly more of
the IUGR males (40% versus 23% for normal birth weight controls) had low
educational achievement defined as education less than 12 years or attending a
special educational school. For females, the rates were 15% versus 6%,
respectively. IUGR birth had no effect on having an IQ < 85 when multivariate
analysis was performed to control for confounding variables such as ethnic
origin, parental education, social class and birth
order.

Effects of IUGR on the development of very low birthweight children

Studies of the effects of intrauterine growth failure among very
low birthweight (VLBW < 1.5 kg) preterm children have mainly pertained to
childhood (Sung et al, 1993; Pena et al, 1988; Robertson et
al, 1990; Calame et al, 1986). Results have been confounded by the
fact that some researchers have compared the children to control children of
similar birthweight, whereas others compared them to control children of similar
gestational age.

Robertson et al (1990) in Canada examined school
performance at 8 years of preterm, small for gestational age VLBW infants and
compared it to that of VLBW children born appropriate for gestational age. The
IUGR children did not differ in school performance when compared to either
birthweight- or gestational-age-matched controls. All the VLBW groups had
significantly inferior outcomes when compared to a normal-birthweight control
group.

In Cleveland we compared the school age outcomes of a cohort of 51
VLBW children who were born IUGR (with birthweights less than-2 SD for
gestational age), to 198 VLBW born appropriate for gestational age. The groups
did not differ in maternal socio-demographic characteristics, with the exception
that more mothers of the appropriately grown (AGA) children were married (67%
vs. 48%, respectively). Mothers of the IUGR children had a significantly higher
rate of pregnancy hypertension. More IUGR than AGA children were multiple births
(31% vs. 9%) and IUGR children had a significantly higher gestational age (32
vs. 29 wks) and lower birthweight (1113 g vs. 1192 g) compared to the AGA
population. The AGA children had significantly more neonatal problems including
lower 5-minute Apgar scores and a higher incidence of respiratory distress
syndrome and apnea of prematurity. The populations thus differed in maternal
marital status, birthweight, gestational age, and the rates of neonatal
problems. No overt intrauterine infections were diagnosed.

At 8 years of age AGA children had higher rates of cerebral palsy
(25% vs. 6%), but this difference was not significant. No significant
differences in intelligence, language, visual-motor abilities, fine motor
abilities, and academic achievement were noted between the AGA and IUGR
children.

Based on the literature reported, we conclude that intrauterine
growth retardation does not appear to impose an added disadvantage at school age
over and above that of very low
birthweight.

Discussion and conclusion

In general, the follow-up studies report overall normal
intelligence with a trend to lower scores among IUGR subjects. Despite the
limitations of the literature reviewed, there is no consistent evidence of a
detrimental effect of IUGR on the mental and behavioral outcomes of adolescents
or adults. The rates of major handicap are low, although there tend to be higher
rates of minimal cerebral dysfunction, as evidenced by learning and subtle
neurological and behavioral problems in IUGR children with normal intelligence.
Three of the studies noted a decrease in the rates of abnormal neurodevelopment
with increasing age (Douglas and Gear, 1976; Hawdon et al, 1990; Westwood
et al, 1983) which could be associated with an amelioration of subtle
neurological dysfunction after the onset of puberty. Support for this hypothesis
is the work of Soorani-Lunsing (1993), who reported that onset of puberty was
associated with a decrease in the rates of neurologic dysfunction, including
fine manipulative disability, coordination problems, choreiform dyskinesia and
hypotonia. She hypothesized that general maturational changes during puberty, as
well as specific hormonal changes in estrogen secretion, might play a role in
improving outcome.

The review of the literature reveals that ongoing detrimental
effects of socio-environmental deprivation throughout the lifespan play a much
greater role in determining outcome than any potential effect of intrauterine
growth failure on the developing nervous system (Douglas and Gear, 1976; Hawdon
et al, 1990; Drillien, 1970; Westwood et al, 1983; Illsley and
Mitchell, 1984; Neligan et al, 1976; Low et al, 1992; Martyn et
al, 1996; Stein et al, 1972). Warshaw (1985) has suggested that
rather than representing serious pathology, IUGR may be an adaptation in which
the size of the fetus is maintained appropriate to the availability of
nutrients. The most consistent biologic predictors of poor later mental
development and behavior in IUGR children are hypoxic ischemic injury and
subnormal brain growth (Westwood et al, 1983; Berg, 1989; Ounsted et
al, 1988; Harvey et al, 1982; Parkinson et al, 1981). Brain
growth, as measured by the sonographic biparietal diameter or by head
circumference after birth, is usually less affected than weight or length,
resulting in "asymmetric" growth failure (Cooke et al, 1977; Kramer et
al, 1989). This "brain sparing" may be protective when growth is restricted
in utero, and outcome may be affected when this mechanism fails. This is
especially evident when brain growth (head size) fails to catch up during
infancy and childhood (Hack et al, 1989, 1991; Babson and Henderson,
1974; Lipper et al, 1981).

Thus, with the exception of extreme IUGR affecting brain growth,
and hypoxic ischemic injury, IUGR seems to have little or no measurable effect
on mental performance and behavior in adolescence or adulthood. However, since
IUGR occurs more often in deprived environmental circumstances, it can serve as
a marker for the associated poor outcomes throughout
life.

Discussion

In follow-up studies of older children it becomes more and more
difficult to separate prenatal and postnatal effects. Other major problems are
diminishing statistical power and potential biases due to sample attrition.

Most studies of long-term outcomes of IUGR are relatively old.
Considerable improvements have been made in the last few years in obstetric and
emergency newborn care in industrialized countries. This means that the factors
that recent survivors have been exposed to and the risks they entail could be
substantially different from those of earlier study populations.

If head sparing can be observed in some IUGR babies, it is usually
relative, i.e. head size is also affected, but to a lesser extent than weight
and height. The extent to which head size is reduced seems closely related to
the degree of growth retardation and no attempt has yet been made to dissociate
the two and their effect on mental and behavioral development.

Effects of IUGR seem closely associated with accompanying factors;
it is not always clear whether these should be treated as confounding factors
and controlled for or not. Factors like socioeconomic status are clearly
confounding factors, because they exist before and after IUGR occurs and are
unlikely to be on the causal pathway between growth retardation and cognitive
outcome. Asphyxia is a transient phenomenon and a factor that is likely to be on
the causal pathway between IUGR and later outcomes. Where it is, at least
partly, avoidable, it is of interest to know what specific outcomes, or what
proportion of them, are attributable to asphyxia. If one wishes to assess the
effect of IUGR in areas where factors like asphyxia are still less amenable to
treatment, it seems more appropriate not to control for them.

Environmental circumstances can both enhance and reduce
developmental differences and other consequences. Mothers have been observed for
instance to react in a dichotomous way to the abnormal cries of malnourished
children, some devoting more time and attention to them, some less. Favorable
socio-economic conditions can have a protective effect, whereas under
unfavorable socioeconomic conditions, adverse effects can be amplified. The
general conclusion from Hack's review of the literature is that, while IUGR can
produce disadvantages in childhood that are significant, at least in statistical
terms, these tend to be most consistent and marked from the preschool years
through adolescence and gradually overridden by environmental influences in the
long-term.Among the commonly used indicators, a length deficit at an early
age seems to be the best predictor of motor and mental development. Effects
associated with ponderal index could be attributable mainly to length or height.
Advocates of ponderal index argue that it provides the best reflection of the
timing of the insult, and that this in turn could be of prognostic
importance.